This Program Project will critically evaluate a hypothesized "cytokine cycle" of molecular and cellular events that is important in the pathogenesis of Alzheimer's disease (AD) and other degenerative conditions that are characterized by glial activation and over-expression of interleukin-1 (IL-1). Neuronal injury, induced by effectors such as trauma, genetics, and aging, results in over-expression of IL-1, which has known leads to further degeneration. IL-1 over-expression results in (i) induction of neuronal over-expression and processing of beta-amyloid precursor protein (betaAPP), leading to Abeta deposition, cell death, and release of secreted APP, each stimulating further over-expression of IL-1); and (ii) activation of astrocytes with synthesis and release of S100beta, increasing the potential for cell death by promoting increases in intraneuronal calcium, promoting synthesis of betaAPP, and inducing over-growth of dy6strophic neurites. We will determine the role of IL-1 genotype in glial inflammatory processes and neuronal cell injury and loss in AD and in conditions that may predispose to AD pathology, e.g., early Braak and Braak stages, epilepsy, and head injury. We will also investigate the possibility that IL-1 driven cascades in muscle contribute to repair and degenerative processes, which include increase expression of betaAPP and other cytokine cycle parallels to neurodegeneration. Moreover, we will investigate the possibility that IL-1 genotype contributes to the variability in muscle adaptation to damaging exercise observed in older subjects. Transgenic animals, over- or not expressing S100beta or IL-1 or carrying human mutated betaAPP or combinations of these genotypes, will be used to define mechanisms responsible for neurodegeneration described above, and to define mechanisms evoked by these genetic variations during aging in muscle. Cell culture models will be used to define mechanisms by which inflammatory proteins may mediate and propagate excitotoxic neuronal cell injury and exercise-induced muscle cell injury and death, and to explore the ameliorating effect of potential or putative therapeutic agents. Accomplishment of the goals of this Program Project will yield results that directly identify basic mechanisms in Alzheimer pathogenesis and provide targets for developing therapeutic strategies for degenerative conditions in general.